The present invention relates to block copolymers for micellar delivery of drugs. It is of particular value for delivery of hydrophobic drugs.
Micelle based drug delivery systems have been developed which are based on amphiphilic copolymers. Such copolymers should have a hydrophobic moiety and a hydrophilic moiety. In a micelle, the hydrophobic moieties aggregate to form a core, with the hydrophilic moieties being revealed at the surface of the micelle where they associate with water. The micelles can solubilise poorly water-soluble drugs in their inner core. Their small size renders them suitable for systemic delivery of drugs. The core-shell structure provides some protection for the drug in the core during transport to a target cell.
Although random copolymers may be used, in which some of the monomers have hydrophobic pendant groups, most work has focussed on block copolymers. AB diblock copolymers and ABA triblock copolymers, A being the hydrophilic block and B being the hydrophobic block have been investigated. In most of the block copolymers tested to date, the hydrophilic blocks have been provided by polyethylene oxide moieties. The hydrophobic block may be a polypropylene oxide block, a hydrophobic polypeptide (such as poly(β-benzyl-L-aspartate)), a polyester (poly(DL-lactic acid)) or poly(ε-caprolactone). Polystyrene and poly(methylmethacrylate) have also been investigated as constituents of the core.
Alakhov et al in Biomedical Polymers and Polymer Therapeutics, 2001, eds Chiellini et al Kluwer Academic/Plenum publishers, New York, 121 to 137, describe the use of polyethylene oxide-polypropylene oxide block copolymers to deliver doxorubicin. Such compounds are commercially available with low poly-dispersity (of molecular weight) under the trade name Pluronic and Poloxamer (trade marks). They investigate the effect of the average molecular weight and the hydrophilic/lipophilic balance (HLB) of the block copolymer upon cytotoxicity against a panel of cell lines.
Jones et al in Eur. J. Pharm. Biopharm. 48 (1999) 101 to 111 review the disclosures of various block copolymers as colloidal drug carriers, and explains various ways in which micelles are formed with hydrophobic drug in the core.
Inoue et al in J. Cont. Rel. 51(1998) 221 to 229 describe an AB block copolymer having amphiphilic properties, in which one block is formed of methyl methacrylate (the hydrophobic core) and the other block is formed of acrylic acid units. Polymerisation is conducted by initially forming an oligomer of methylmethacrylate units, and using this as the initiator for polymerising a block of acrylic acid. The average molecular weight of the hydrophobic block was said to be 4300, although the molecular weight of the block copolymer was not stated. The physical form of the drug delivery system appeared to involve non-micellar structures, termed “unimers”.
In our earlier applications No WO-A-0228929, not published at the priority date hereof we described the polymerisation of zwitterionic monomers by atom transfer radical polymerisation techniques, some of the polymers were block copolymers. A general suggestion was made that the polymers may have utility in delivery of drugs.